Transcranial magnetic Stimulation (TMS) is the leading noninvasive device for the stimulation of brain and nerve activity. As such, a significant increase in the variety of applications for TMS, from therapeutic treatments for depression or migraine to probing brain activity in a large number of research topics is seen. TMS is a novel and innovative addition to the arsenal of noninvasive probing capabilities and intervention modalities. The development of such probes is one of the major issues of diagnostic and therapeutic approaches to neurology and neurosurgery. The major limitation of TMS is the precision and specificity of its activation region. TMS is currently able to excite only specific areas in the brain, mostly in the cortex. It is still not obvious what determines the accessibility of brain areas to magnetic stimulation.
Transcranial Magnetic Stimulation (TMS) is a noninvasive technology for stimulating the brain that shows much promise for both research and clinical use. However, the basic technology has basically remained unchanged, and advances in its application have been far and few. Recent developments have concentrated both on the ability to deliver pulses at a high frequency repetition rate and on reaching deeper regions of the brain. This has been motivated in part by the hope of replacing the effective yet highly intrusive Electro Convulsive Therapy (ECT) for depression that is not responsive to drugs. However, a main limitation of TMS at this stage of its development is the highly specific directionality of the applied field, which demands a precisely targeted application that is extremely sensitive to motion and disturbances. Both location and orientation must be determined with high resolution and once an optimal position is determined, the magnet must be kept there during all the treatment. Stable and reproducible positioning can be achieved using MRI imaging and stereotactic positioning, but a device that ameliorates the directional sensitivity and enables a more efficient mode of applying TMS is a goal for development of future magnets.
The directional sensitivity arises because neurons are excited only if their axons are directed precisely along the induced electric field.
It was recently demonstrated that neuronal cultures are a major enabling tool for the development of TMS, with which new magnets, drug and TMS combination treatments, new protocols and other innovations can be screened and tested with no need for animal or human subjects. The ability to create action potential responses in cultures relies on two properties, namely size and orientation.
The dependence on orientation arises because the magnetic stimulation of a neuron occurs at the axon, whose projection along the induced electric field is the relevant parameter for achieving excitation. Using quasi-one-dimensional patterned cultures, axons could be directed to grow along rings concentric with the magnet, thus forcing them to have an extensive projection along the induced electric field. It should be noted that if it was possible to excite neurons by initiating an action potential in the dendrites then the situation would change, and the directionality would not be as crucial. Embodiments of such excitation are described herein below.
Another important feature that has been identified is that the initial excitation is achieved by stimulating a sub-population of especially sensitive neurons, which then serve as a nucleating center for the firing of the whole network. In a culture that has been completely disconnected by applying receptor antagonists (CNQX, APV and Bicuculline), only this small subset (about 1 percent) is active and responds to magnetic stimulation. When the culture is connected, this kernel is responsible for eliciting a population response of all neurons in the network. If the size of the kernel is too small, the driving input into neurons in the network is not enough for initiating the population response.
To achieve a population response to magnetic stimulation, one must therefore excite action potentials in a large number of initiating neurons. In a neuronal network whose axonal orientation is random, this requirement is difficult to meet using conventional TMS, since the orientation of its induced field is constant and the probability that a large enough number of axons will be directed along this field is low.